EP2248807B1 - N-phenyl-2-pyrimidine-amine derivatives - Google Patents

N-phenyl-2-pyrimidine-amine derivatives Download PDF

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Publication number
EP2248807B1
EP2248807B1 EP10171388.1A EP10171388A EP2248807B1 EP 2248807 B1 EP2248807 B1 EP 2248807B1 EP 10171388 A EP10171388 A EP 10171388A EP 2248807 B1 EP2248807 B1 EP 2248807B1
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EP
European Patent Office
Prior art keywords
free
methyl
amino
substituted
lower alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP10171388.1A
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German (de)
English (en)
French (fr)
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EP2248807A1 (en
Inventor
Olivier Loiseleur
Daniel Kaufmann
Stephan Abel
Hans Michael Buerger
Mark Meisenbach
Beat Schmitz
Gottfried Sedelmeier
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Novartis Pharma GmbH
Novartis AG
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Novartis Pharma GmbH
Novartis AG
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Priority to SI200332291T priority Critical patent/SI2248807T1/sl
Publication of EP2248807A1 publication Critical patent/EP2248807A1/en
Application granted granted Critical
Publication of EP2248807B1 publication Critical patent/EP2248807B1/en
Priority to CY20131100686T priority patent/CY1114351T1/el
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to the use of certain N-phenyl-benzamides for the preparation of N-(2-pyrimidinamino-phenyl)-benzamides and a process for the preparation of N-(2-pyrimidinamino-phenyl)-benzamides.
  • the present invention relates to the use of N-phenyl-benzamides of formula I wherein one of the radicals R 1 , R 2 , R 3 , R 4 and R 5 is
  • lower within the scope of this application denotes radicals having up to and including 7, preferably up to and including 4 carbon atoms, preferably methyl or ethyl.
  • lower fluorinated alkyl within the scope of this application denotes radicals having up to and including 7, preferably up to and including 4 carbon atoms, preferably methyl or ethyl, which are substituted by fluorine such as mono, di or trifluoro-methyl, trifluoro-ethyl.
  • piperazinyl within the scope of this application denotes unsubstituted piperazinyl or N-lower alkyl-piperazinyl such as 4-methyl-piperazinyl-.
  • Halogen is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
  • Etherified hydroxy is preferably lower alkoxy.
  • Esterified hydroxy is preferably hydroxy esterified by an organic carboxylic acid, such as a lower alkanoic acid, or a mineral acid, such as a hydrohalic acid, for example lower alkanoyloxy or especially halogen, such as iodine, bromine or especially fluorine or chlorine.
  • Alkylated amino is, for example, lower alkylamino, such as methylamino, or di-lower alkylamino, such as dimethylamino.
  • Acylated amino is, for example, lower alkanoylamino or benzoylamino.
  • Esterified carboxy is, for example, lower alkoxycarbonyl, such as methoxycarbonyl.
  • R 3 is lower alkyl substituted by benzylamino, benzoylamino, halogene, pyrrolidinyl, piperidyl, piperazinyl, e.g. 4-methyl-piperazinyl-, or morpholinyl, thiomorpholinyl , the substituents of said substituted radical being selected from the group consisting of cyano; lower alkyl; hydroxy- or amino-substituted lower alkyl; trifluoromethyl; free, etherified or esterified hydroxy; lower alkoxy; lower alkanoyloxy; free, alkylated or acylated amino; mono- or di-lower alkylamino; lower alkanoylamino; benzoylamino; free or esterified carboxy; lower alkoxycarbonyl and halogen.
  • R 3 is lower alkyl substituted by pyrrolidinyl, piperidyl, piperazinyl, e.g. 4-methyl-piperazinyl-, or morpholinyl, thiomorpholinyl, the substituents of said substituted radical being selected from the group consisting of lower alkyl; hydroxy- or amino-substituted lower alkyl;
  • R 1 , R 2 , R 4 , R 5 and R 8 are hydrogen.
  • R 7 is lower alkyl such as methyl or fluorinated alkyl such as trifluoromethyl.
  • R 3 is (4-methyl-piperazinyl)-methyl
  • R 1 , R 2 , R 4 , R 5 and R 8 are hydrogen
  • R 6 is halogen
  • R 7 is methyl.
  • the invention relates to the use of amides of formula I, wherein R 1 , R 2 , R 4 , R 5 and R 8 are hydrogen, R 3 is (4-methyl-piperazinyl)-methyl, R 6 is Br, Cl, NH 2 , NO 2 , NHC(O)CF 3 , NHC(O)CH 3 , or NHC(NH)NH 2 , and R 7 is methyl, for the preparation of compound of formula IV, wherein R 1 , R 2 , R 4 , R 5 and R 8 are hydrogen, R 3 is (4-methyl-piperazinyl)-methyl, R 6 ' is 4-(3-pyridyl)-2-pyrimidinamino, and R 7 ' is methyl, or a pharmaceutically acceptable salt or crystal form thereof.
  • Amides of formula I may be prepared by a process as depicted below: wherein R 1 to R 8 are as defined above and R 9 is hydrogen, methyl, ethyl or aryl.
  • Direct conversion of unactivated carboxylic acids or esters to amides, such as compounds of formula II, with amines typically requires high reaction temperature, e.g. of about 200°C, or use of strong bases, such as sodium methoxide, sodium amide, n -butyl lithium, sodium hydride or Grignard reagent.
  • Compounds of formula IV inhibit the tyrosine kinase activity of the receptor for the epidermal growth factor (EGF) and are useful, inter alia, for the treatment of benign or malignant tumors. They are able to effect tumour regression and to prevent metastatic spread and the growth of micrometastases. In particular, they can be used for treating epidermal hyperproliferation (psoriasis), for treating neoplasms of epithelial character, e.g. mastocarcinoma, and leucemia. In addition, the compounds of formula IV are useful for treating diseases of the immune system and inflammations, subject to the involvement of protein kinases. The compounds of formula IV may also be used for treating diseases of the central or peripheral nervous system, subject to the involvement of signal transmission by protein kinases.
  • EGF epidermal growth factor
  • the present invention relates to a process for the preparation of a compound of formula IV wherein R 1 , R 2 , R 4 and R 5 are independently
  • reaction is carried out in a polar organic solvent such as n-butanol.
  • a polar organic solvent such as n-butanol.
  • R 11 is methyl and preferably R 1 , R 2 , R 4 and R 5 are all hydrogen.
  • the compound of formula I wherein R 6 is NHC(NH)NH 2 , R 7 is methyl and R 8 is hydrogen may e.g. be treated with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one to a compound of formula IV wherein R 6 ' is 4-(3-pyridyl)-2-pyrimidinamino, R 7 ' is methyl and R 8 ' is hydrogen, corresponding to the compound of formula IV as described in example 21 of EP 564 409 .
  • a compound of formula I wherein R 6 is Br, R 7 is methyl and R 8 is hydrogen may e.g. be treated with 4-(3-pyridyl)-2-pyrimidine-amine, e.g. as available from Chempacific, in the presence of Pd(0) or PD(II) in the presence of a phosphine ligand to give compound of formula IV wherein R 6 ' is 4-(3-pyridyl)-2-pyrimidinamino, R 7 ' is methyl and R 8 ' is hydrogen.
  • compounds of formula I wherein R 6 is NO 2 , R 7 is methyl and R 8 is hydrogen may e.g. be transformed to a compound of formula I wherein R 6 is NH 2 , R 7 is methyl and R 8 is hydrogen using standard methods known to the skilled person.
  • the processes of the present invention allow the synthesis of compounds of formula IV, preferably a compound of formula IV wherein R 1 , R 2 , R 4 , R 5 and R 8 ' are hydrogen, R 3 is (4-methyl-piperazinyl)-methyl, R 6 ' is 4-(3-pyridyl)-2-pyrimidinamino, and R 7 ' is methyl, in a more efficient and higher yielding manner than previously described in the literature e.g. in EP 564409 . No expensive coupling reagents have to be used. The higher throughput combined with less steps as in the prior art will result in significantly lower production costs In the previously described syntheses, mutagenic intermediates may be formed.
  • AlMe 3 trimethylaluminium from FLUKA Al(iBu) 3 triisobutylaluminium from FLUKA AlCl 3 aluminium trichloride from Merck platinum on sulfide carbon from Acros thionyl chloride from FLUKA Celite Filter Cel from FLUKA Rochelle Salt potassium-sodium tartrate from FLUKA platinum on carbon from Engelhardt cyanamide from FLUKA 3-dimethylamino-1-pyridin-3-yl-propenone from FLUKA sodium- tert .-butylate from FLUKA rac -BINAP 2,2'-bis-(diphenylphosphino)-1,1'-binaphthalin synthesized according to literature procedure tris(dibenzylideneacetone)-dipalladium chloroform complex Pd 2 (dba) 3 *CHCl 3 from FLUKA
  • 4-(4-Methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester is obtained as follows: A solution of 4-formyl-benzoic acid methyl ester (10.0 g, 61 mmol) in methanol (100 ml) is treated sequentially with 1-methylpiperazine (6.7 g, 67 mmol) and platinum (5%) on sulfided carbon (0.5 g). The resulting solution is then heated at 90°C and is subjected to a pressure of 5 bar of hydrogen for a period of 4 hrs until the hydrogen uptake is complete. The reaction mixture is cooled to room temperature and filtrated over a pad of Celite. The methanol is removed under reduced pressure and replaced with toluene (100 ml).
  • 4-methyl-3-nitroaniline (30.0 g, 0.197 mol) is added to a mixture of tetrahydrofuran (120 ml) and N -ethyl- N , N -diisopropyl-amine at 23-25 °C over a period of 5 to 10 min.
  • chloromethyl-benzoylchloride 38.4 g, 0.20 mol
  • tetrahydrofuran 35 ml
  • the intermediate N-(4-methyl-3-nitro-phenyl)-4-chloromethyl-benzamide can be isolated by distilling of half of the tetrahydrofuran under reduced pressure and adding the residue to water (300 ml) at a temperature of 20-25 °C over a period of 30 min. After stirring for another 30 min at 0-5 °C, the suspension is filtered, washed with water (200 ml) and dried in vacuo. The intermediate is dissolved in tetrahydrofuran (150 ml) and added to N-methylpiperazine (138.2g, 1,38 mol) over a period of 60 to 90 min maintaining a temperature of 25-30 °C.
  • N-methylpiperazine 138.2g, 1,38 mol
  • a suspension of 4-formyl-benzoic acid (10.0 g, 67 mmol) in methanol (100 ml) is treated sequentially with 1-methylpiperazine (7.3 g, 73 mmol) and platinum (5%) on sulfided carbon (1 g).
  • the resulting suspension is then heated at 80°C and is subjected to a pressure of 5 bar of hydrogen for a period of 20 hrs until the hydrogen uptake is complete.
  • the reaction mixture is cooled to room temperature and filtrated over a pad of Celite. Water (20 ml) is used to rinse the reactor and dissolve the fraction of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid that crystallizes on the walls during the cooling of the reaction mixture.
  • reaction mixture is then cooled to 0°C and quenched by slow addition of a saturated aqueous solution of Rochelle salt (70 ml) which causes the precipitation of the crude product.
  • a saturated aqueous solution of Rochelle salt 70 ml
  • t -Butyl methyl ether 150 ml
  • methylene chloride 100 ml
  • aqueous saturated NaHCO 3 100 ml
  • aqueous saturated NaCl 100 ml
  • the aqueous phases are back-extracted with t- butyl methyl ether (100 ml).
  • Butyl acetate (60 ml) is added dropwise at 100°C and the solution is cooled to 0°C within 1 hr and stirred at 0°C for 16 hrs. The resulting deep orange suspension is filtered off with suction, the isolated solid is washed with n-butanol (2 x 50 ml) and water (2 x 50 ml) and dried in vacuo at 60°C. Yield: 36.4 g of the title compound, 93% based on theory, as off-white crystals. (99.6% area by HPLC).
  • a suspension of N -(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide (50 g, 144 mmol) in n-butanol (300 ml) at 85°C is treated sequentially with concentrated aqueous HCI until the pH reaches 2.5 (HCI 37%, 35 g) and with a solution of cyanamide (12.1 g, 288 mmol) in water (12 ml) over a period of 30 min.
  • the resulting reaction mixture is stirred at 85°C for 20 hrs during which time the starting material dissolves and the desired product crystallizes out of solution as the di-hydrochloride salt.
  • the di-hydrochloride salt is dissolved in water (250 ml) at 35°C.
  • An aqueous solution of NaOH (2N, 150 ml) is added and the pH of the solution increases to 13.2.
  • the desired product separates from the aqueous solution as an oil which crystallizes upon cooling to 0°C.
  • the product is filtered off, washed with an aqueous solution of K 2 CO 3 (5.5 g/L, 2 x 50 ml) and dried in vacuo at 50°C. Yield: 41.2 g of the title compound, 89% of theory based on the intermediate di-hydrochloride salt, as beige crystals, (98.7% area by HPLC).
EP10171388.1A 2002-02-07 2003-02-06 N-phenyl-2-pyrimidine-amine derivatives Expired - Lifetime EP2248807B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
SI200332291T SI2248807T1 (sl) 2002-02-07 2003-02-06 N-fenil-2-pirimidin-aminski derivati
CY20131100686T CY1114351T1 (el) 2002-02-07 2013-08-09 Παραγωγα ν-φαινυλ-2-πυριμιδινης-αμινης

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0202873.6A GB0202873D0 (en) 2002-02-07 2002-02-07 Organic compounds
EP03737319A EP1474408B1 (en) 2002-02-07 2003-02-06 N-phenyl-2-pyrimidine-amine derivatives

Related Parent Applications (1)

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EP03737319.8 Division 2003-02-06

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EP2248807A1 EP2248807A1 (en) 2010-11-10
EP2248807B1 true EP2248807B1 (en) 2013-07-03

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EP10171388.1A Expired - Lifetime EP2248807B1 (en) 2002-02-07 2003-02-06 N-phenyl-2-pyrimidine-amine derivatives
EP03737319A Expired - Lifetime EP1474408B1 (en) 2002-02-07 2003-02-06 N-phenyl-2-pyrimidine-amine derivatives

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US (8) US7456283B2 (es)
EP (2) EP2248807B1 (es)
JP (2) JP4653954B2 (es)
KR (1) KR101027044B1 (es)
CN (2) CN100347162C (es)
AU (1) AU2003244444B2 (es)
BR (2) BR0307529A (es)
CA (2) CA2474738C (es)
CO (1) CO5601018A2 (es)
CY (2) CY1112938T1 (es)
DK (2) DK2248807T3 (es)
EC (2) ECSP045220A (es)
ES (2) ES2425980T3 (es)
GB (1) GB0202873D0 (es)
HK (2) HK1145322A1 (es)
IL (3) IL163158A (es)
MX (1) MXPA04007642A (es)
NO (2) NO327366B1 (es)
NZ (3) NZ534315A (es)
PL (1) PL209475B1 (es)
PT (2) PT1474408E (es)
RU (2) RU2370493C2 (es)
SG (1) SG160195A1 (es)
SI (2) SI2248807T1 (es)
WO (1) WO2003066613A1 (es)
ZA (1) ZA200405970B (es)

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